33 Thus, it is an apparent paradox that in DEN-exposed mice an increased as well as decreased β-catenin expression appears to enhance the susceptibility to HCC. A surprising and unexpected result of our study was that β-catenin mutations are comparatively late events and that chromosomal instability clearly precedes the occurrence INCB018424 mouse of β-catenin mutations. In tumors at weeks 32-42 there was no clear correlation between β-catenin mutation status and chromosomal instability.
Thus, β-catenin mutations do not appear to be the driving force behind chromosomal instability in this mouse model. The apparent lack of correlation between β-catenin mutations and chromosomal instability may explain why, in contrast to previous reports,35, 36 our tumors with β-catenin mutations clearly show chromosomal instability. Importantly and also in contrast to previous
work, β-catenin-activating mutations are—at least in the DEN model—not involved in HCC initiation but rather in tumor progression, which may explain the differences reported in the two aforementioned studies.32, 33 In Dorsomorphin cost summary, our study suggests that the majority of the current knowledge about genomic changes in HCC is based on advanced tumor lesions and that systematic analyses of the chronologic order including early lesions may reveal new, unexpected findings. Such findings include that at least in the DEN-induced HCC mouse model β-catenin mutations are not early events and that these mutations occur independently of chromosomal instability. Loss of the distal region of the mouse chromosome 4q, which is syntenic to the distal human 1p region, is likely an early driver mutation. The loss of the known tumor suppressor genes Runx3 and Nr0b2/Shp within this region Mannose-binding protein-associated serine protease may be critical in the initiation or first steps
in HCC development. We thank Prof. Michael Trauner and Dr. Johannes Haybaeck for critically reading the article and stimulating discussions. We thank Mag. Maria Langer-Winter for editing the article. We thank Dusan Babic for expert help in the preparation of the figures and Dr. Ivan Kanchev for help with pathologic samples. The help of Dr. Walter Spindelböck with the statistical analysis is highly appreciated. Additional Supporting Information may be found in the online version of this article. “
“Nonalcoholic fatty liver disease (NALFD) encompasses a wide spectrum of liver injury ranging from bland hepatic steatosis to nonalcoholic steatohepatitis (NASH). Bland steatosis follows a relatively benign clinical course, but NASH may progress to cirrhosis. NAFLD affects about one third of the adult US population and up to 10% of children and teenagers. The demographics of NAFLD in the general population mirrors that of the metabolic syndrome, which is characterized by obesity, diabetes, hypertension, and dyslipidemia.